Naphthyridine derivatives

ABSTRACT

The present invention relates to new indolo [3,2,1-de]-[1,5]naphthyridine derivatives and their addition salts with pharmaceutically acceptable acids, the preparation of such derivatives and salts and medicaments in which they are present as active principle.

The present invention relates to new indolo[3,2,1-de][1,5]naphthyridinederivatives and their addition salts with pharmaceutically acceptableacids, the preparation of such derivatives and salts and medicaments inwhich they are present as active principle.

The invention provides naphthyridine derivatives in the form ofracemates or optical isomers corresponding to the formula: ##STR1##wherein R₁ represents a hydrogen atom or a group chosen from alkylgroups with 1 to 4 carbon atoms, 2-oxo-propyl, 2-hydroxy-propyl,3-oxo-butyl, 3-hydroxy-butyl, cyclopropylmethyl, benzyl, halogenobenzyl(preferably fluorobenzyl or chlorobenzyl), acetyl, cyclopropylcarbonyland benzoyl groups, and --(CH₂)_(n) --R' groups where n is 1 or 2 and R'represents a methoxycarbonyl, ethoxycarbonyl or cyano group, R₂represents a hydrogen atom, a halogen atom, or a methyl or methoxygroup, R₆ represents a hydrogen atom or a COR₇ group, R₇ being ahydroxyl group, an alkoxy group with 1 to 4 carbon atoms, or an amino,methylamino, dimethylamino or cyclopropylamino group, and either R₃represents a methyl or ethyl group, R₄ represents a hydrogen atom or ahydroxyl group and R₅ represents a hydrogen atom, or R₃ and R₄ togetherrepresent an oxygen atom and R₅ represents a hydrogen atom, or R₃represents a methyl or ethyl group and R₄ and R₅ together represent anadditional carbon-carbon bond, with the exception of the compoundswherein R₃ and R₄ are oxygen, and either R₁ is H, R₂ is CH₃ O in the10-position and R₆ is H, or R₁ is H, R₂ is H and R₆ is H, and thestereoisomers of the compounds for which R₆ is an alkoxycarbonyl group,and addition salts of the compounds (I) with pharmaceutically acceptableorganic or inorganic acids.

The compounds of the formula (I) and their salts can be used asmedicaments in human and veterinary medicine.

All the compounds of the invention have two optical isomers, namely thed and l isomers, since the carbon atom in the 3a position is in effectasymmetrical. In the examples below racemates of the compounds areobtained.

Furthermore, the compounds I for which R₆ is an alkoxycarbonyl radicalexhibit cis/trans isomerism relative to the bond between positions 3aand 4, the cis and trans isomers being separable by columnchromatography.

One group of valuable compounds consists of compounds for which R₁ is ahydrogen atom, an alkyl group with 1 to 4 carbon atoms, a 3-oxo-butylgroup, a 3-hydroxy-butyl group, a 2-oxo-propyl group, a 2-hydroxy-propylgroup or a methoxycarbonylethyl group, R₂ is a hydrogen atom, a halogenatom, a methyl group or a methoxy group, R₆ represents a hydrogen atom,a methoxycarbonyl group, an ethoxycarbonyl group, or acyclopropylaminocarbonyl group, and R₃, R₄ and R₅ and the exceptions areas defined above.

Preferred compounds of the invention are those for which R₃ and R₄together represent an oxygen atom and R₅ is a hydrogen atom.

The compounds of the invention may be prepared by a process whereintryptamine or one of its derivatives of the formula: ##STR2## in which Ris H, alkyl, cycloalkyl or optionally substituted benzyl, and R₂ has themeaning given above, is condensed with a carbonyl derivative of a diacidor its aliphatic diester, such as glutaric acid having a ketone group inthe α-position or succinic acid having an aldehyde group in theα-position, thereafter cyclisation is carried out to form theindolo[3,2,1-de][1,5]naphthyridine nucleus, the substitution and/ordegree of saturation of this nucleus being thereafter modified asdesired by methods known per se.

The reaction schemes below show the principal methods for thepreparation of the compounds of the formula (I). ##STR3##

The reduction is preferably carried out in a low molecular weightalcohol, using an alkali metal borohydride, at ambient temperature.

The two diastereoisomers are separated by chromatography. ##STR4##

Hydrolysis of the ester and conversion of the acid hydrochloride to thenon-salified free acid are carried out according to conventionalmethods. ##STR5##

The acid chloride is preferably obtained using thionyl chloride and theconversion to the amide is carried out in the conventional way.

In the schemes above, R₁, R₂, R₃, R₆, R₇, R' and n have the meaningsalready specified in connection with the formula (I), R₈ represents analkyl radical with 1 to 4 carbon atoms, especially an ethyl radical, R₉represents a hydrogen atom, an alkyl radical containing 1 to 3 carbonatoms, a cyclopropyl radical, a phenyl radical or a halophenyl radical,R₁₀ represents a methyl, cyclopropyl or phenyl radical and X representsa halogen atom, especially chlorine, bromine or iodine.

The non-limiting Examples below illustrate the way in which theinvention is carried out and give details of the methods shown inschemes A to L.

The scheme A₁ method (1st cyclisation method) was substantially carriedout in the way described by TABORSKY and Mc ISAACS (J. Med. Chem. 1964,7, 135) for similar compounds. It is not reproduced here.

The IR and NMR spectra, as well as the analyses, confirm the structureof the compounds.

EXAMPLE 1 Methyl1,2,3,3a,4,5-hexahydro-3-methyl-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-4-carboxylateand its methanesulphonate [Method A₂ ]

[R₁ =CH₃, R₂ =H, R₃ +R₄ =O, R₅ =H and R₆ =COOCH₃ ]

Cis and trans isomers

60 g (0.30 mol) of diethyl α-formyl-succinate, prepared according to themethod described by PAYOT and CROB (Helv. Chim. Acta 1954, 37, 1269) orTOCANNE and ASSELINEAU (Bull. Soc. Chim. Fr. 1965, 3346), are added to asolution of 48 g (0.28 mol) of N₆ -methyl-tryptamine in 2 l of benzene.

The solution obtained is stirred vigorously for one hour and then it isheated at the reflux temperature for 4 hours, removing the water formedby means of a Dean-Stark apparatus. After cooling, 1 liter of 3 Nhydrochloric acid is added to the solution, the mixture is stirred verybriskly for 1/4 hour and subsequently it is rendered alkaline with adilute solution of ammonia. The organic and aqueous phases are separatedand the latter is extracted several times with ethyl acetate.

After combining the organic phases, they are washed several times withwater and then dried over sodium sulphate and the solvent is evaporatedunder reduced pressure. 70 g, namely a yield of 65-70%, of an oil arethus obtained, which solidifies on scraping. The compound is a mixtureof two isomers, namely cis and trans, as was shown by thin layerchromatography and the NMR spectrum. It is an intermediate diester,derived from 1,2,3,4-tetrahydro-3-methyl-pyrido-[3,4-b]indole ##STR6##

The crude compound is used for the stage which follows. However, asample was purified for analysis, by recrystallisation from petroleumether. It melts at 92° C.

A solution of 6 g (0.016 mol) of the above crude diester in 125 ml ofmethanol is introduced into a reaction apparatus under pressure. Thissolution is saturated at 0° with hydrogen chloride gas and then heatedfor 20 hours in an autoclave at 120° C.

After cooling, the reaction mixture is poured into a solution of ammoniaand extracted several times with ethyl acetate. The extract is washedwith water, dried over sodium sulphate and evaporated under reducedpressure. An oily residue is obtained which is chromatographed on acolumn of silica gel with methylene chloride containing 10 to 15% ofacetone as the eluant.

The compound which is eluted first is the cis-3a,4-H,H isomer. It isobtained with a yield of 48 to 50%. It melts at 205° C.

The compound which is eluted second is the trans-3a,4-H,H isomer. It isobtained with a yield of 20 to 25%. It melts at 163° C.

One equivalent of methanesulphonic acid in solution in ethyl acetate isadded dropwise to a solution of the cis isomer base in the same solvent.

After stirring for 30 minutes, the precipitate is filtered off andrecrystallised from ethanol. Melting point >270° C. It is obtained witha yield of 75 to 85%.

In the same way the methane-sulphonate of the trans-isomer base isobtained, which melts at 257°-258° C.

EXAMPLE 2 Methyl1,2,3,3a,4,5-hexahydro-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-4-carboxylate(method A₂)

[R₁ =R₂ =H, R₃ and R₄ =O, R₅ =H and R₆ =COOCH₃ ]

cis and trans isomers

1. 23 g (0.14 mol) of tryptamine are dissolved hot in 100 ml ofanhydrous methanol, the solution is cooled and then a solution of 30 g(0.15 mol) of diethyl α-formylsuccinate in 50 ml of anhydrous methanolis added dropwise with stirring. Stirring is maintained for 1 hour afterthe end of the addition, the solution is cooled to 0° and 75 ml ofconcentrated sulphuric acid (density=1.84) are added whilst maintainingthe mixture at 0°.

The reaction is terminated by heating the reaction mixture for 1 hour at100°. The reaction mixture is cooled, poured into 1.5 liters of icedwater and filtered to remove a pinkish flocculent precipitate, and thefiltrate is neutralised with 150 ml of 28% strength ammonia, in such away that the internal temperature of the mixture does not exceed 10° to15°. The precipitate which forms is extracted with methylene chlorideand the combined organic extracts are washed with water and dried overanhydrous sodium sulphate. The extracts are filtered, the solvent isevaporated and the gummy residue (weight: 39 g, yield=98%) ischromatographed on two kilos of Merck silica (0.063-0.2) with amethylene chloride-acetone (7:3) mixture.

14 g (yield=37%) of a first product are collected, which melts at 166°C. and then, on eluting with acetone, 14.6 g (yield=38%) of a secondproduct are collected, which melts at 195° C.

The nuclear magnetic resonance spectra show that the two compounds aregeometric isomers, the isomer which melts at 166° having thetrans-structure, whilst the isomer which melts at 195° has thecis-structure.

These are the cis- and trans-isomers of 4-methyl1,2,3,3a,4,5-hexahydro-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-carboxylate.

EXAMPLE 31,2,3,3a,4,5-Hexahydro-3-methyl-6H-indolo[3,2,1-de][1,5]naphthyridin-6-oneand its methanesulphonate (method B)

[R₁ =CH₃, R₂ =H, R₃ +R₄ =O, R₅ =R₆ =H]

2.26 g (0.010 mol) of1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one(obtained in accordance with scheme A₁), 3 g (0.059 mol) of 98% strengthformic acid and 2.5 g (0.024 mol) of 30% strength formaldehyde areintroduced into a 50 ml flask, with stirring.

The solution obtained is heated to the reflux temperature and then leftfor 16 hours at the temperature of the laboratory. Thereafter, thereaction mixture is poured into 250 ml of water and the resultingmixture is washed twice, each time with 100 ml of benzene. The aqueousphase is rendered alkaline with sodium carbonate, which inducescrystallisation.

The product is recrystallised from the minimum quantity of diisopropylether and 1.2 g of1,2,3,3a,4,5-hexahydro-3-methyl-6H-indolo[3,2,1-de][1,5]naphthyridin-6-oneare collected, melting at 95° C. The yield is about 50% and thestructure was confirmed by the IR and NMR spectra.

In order to prepare the methanesulphonate, 5 g (0.0208 mol) of the abovecompound are suspended in 50 ml of methanol and 2.110 g (namely a 10%excess) of methanesulphonic acid are added. The solution obtained isstirred for 15 minutes and 500 ml of anhydrous diethyl ether are addeddropwise thereto, which induces copious crystallisation. After stirringfor one hour, the methane-sulphonate crystals are filtered off andrecrystallised from the minimum quantity of isopropanol and 6.3 g of1,2,3,3a,4,5-hexahydro-3-methyl-6H-indolo[3,2,1-de][1,5]napthyridin-6-oneare collected, melting at 188°. The yield is 85%.

EXAMPLE 41,2,3,3a,4,5-Hexahydro-3-cyclopropylmethyl-6H-indolo[3,2,1-de][1,5-naphthyridin-6-one(method C) ##STR7## R₂ =H, R₃ +R₄ =O, R₅ =R₆ =H]

A solution of 33.8 ml (0.430 mol) of cyclopropanecarboxylic acid in 500ml of benzene is introduced into a 1 liter 3-necked flask, equipped witha stirrer, and 5 g (0.130 mol) of sodium borohydride are added to thesolution. in small portions, in such a way that the temperature neverexceeds 25° C. This addition operation requires about 4 hours.Thereafter, the mixture is left standing overnight at ambienttemperature.

The next day, 5.5 g (0.0243 mol) of1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one areadded to the above solution, all at once, and the mixture is heated for5 hours at the reflux temperature.

After cooling, 500 ml of water and sufficient sodium carbonate to givean alkaline pH are added to the reaction mixture. The benzene phase isseparated off, the aqueous phase is extracted twice, each time with 100ml of benzene, and the extracts are combined with the original phase.This solution is washed with water, dried over sodium sulphate, filteredand concentrated to dryness. The residue is an oil which crystallises onthe addition of diisopropyl ether. The product is recrystallised twicefrom the minimum quantity of this ether and 3.2 g of1,2,3,3a,4,5-hexahydro-3-cyclopropylmethyl-6H-indolo[3,2,1-de][1,5]naphthyridin-6-oneare collected, melting at 126° C.

Thin layer chromatography reveals a single spot.

EXAMPLE 51,2,3,3a,4,5-Hexahydro-3-(2-cyano-ethyl)-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one(methods D and E)

[R₁ =--CH₂ --CH₂ --C.tbd.N, R₂ =H, R₃ +R₄ =O, R₅ =R₆ =H]

(1) Method D

5 g (22 millimols) of1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one insolution in 100 ml of methyl ethyl ketone are introduced into a 250 mlflask with stirring, together with 4.7 g (44 millimols) of sodiumcarbonate, and the mixture is heated under reflux for 1 hour. 8 g (60millimols) of bromopropionitrile and 5 g (30 millimols) of potassiumiodide are then added to this suspension which is maintained underreflux for a further 48 hours. The reaction mixture is cooled, theinorganic salts are filtered off, the filtrate is evaporated to drynessand a residue is obtained which, after passing through a column of 140 gof Merck 7734 silica gel in a 7:3 mixture of the solvents benzene andEtOH, provides 4.3 g of a compound which melts at about 155° C.

After 2 recrystallisations, namely hot and cold, 2.7 g (yield 44%) of1,2,3,3a,4,5-hexahydro-3-(2-cyanoethyl)-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one,melting at 156°-157° C., are isolated.

(2) Method E

4.52 g (0.020 mol) of1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one, insuspension in 30 ml of anhydrous ethanol and 3 ml of acrylonitrile areintroduced, under an atmosphere of nitrogen, into a 100 ml flaskequipped with a stirrer.

The mixture is maintained for 24 hours at the reflux temperature. Oncooling, crystallisation is observed. The precipitate is filtered offand recrystallised from the minimum quantity of anhydrous ethanol. 3.4 gof1,2,3,3a,4,5-hexahydro-3-(2-cyano-ethyl)-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one,melting at 157°-158°, are collected. This compound has the sameproperties as that obtained by method D.

EXAMPLE 61,2,3,3a,4,5-Hexahydro-3-benzoyl-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one(method F)

[R₁ =C₆ H₅ CO, R₂ =H, R₃ +R₄ =O, R₅ =R₆ =H]

4 g (0.017 mol) of1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one in 100ml of anhydrous tetrahydrofurane, 2 ml of pyridine and 4 ml of benzoylchloride are introduced into a 250 ml flask and the mixture is stirredfor 16 hours at 20°.

The pyridine hydrochloride which forms during the reaction is filteredoff and then the filtrate is washed with water until the washing watersare neutral. The filtrate is then dried over sodium sulphate, filteredand evaporated to dryness. The crystals obtained are taken up inpetroleum ether and then recrystallised from the minimum quantity ofmethanol. 4.8 g (yield 82%) of1,2,3,3a,4,5-hexahydro-3-benzoyl-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one,melting at 171°-172° C., are collected.

EXAMPLE 71,2,3,3a,4,5-Hexahydro-3,6-dimethyl-6-hydroxy-6H-indolo[3,2,1-de][1,5]naphthyridine(method G)

[R₁ =CH₃, R₂ =H, R₃ =CH₃, R₄ =OH, R₅ =R₆ =H]

Methyl-magnesium iodide is prepared in the usual way starting from 5 gof magnesium turnings, 75 ml of anhydrous diethyl ether and 11 ml (25 gor 0.420 mol) of methyl iodide.

5 g (0.028 mol) of1,2,3,3a,4,5-hexahydro-3-methyl-6H-indolo[3,2,1-de][1,5]naphthyridin-6-onein solution in 50 ml of anhydrous tetrahydrofurane are added dropwise,under an atmosphere of nitrogen and at a rate such that the temperaturedoes not exceed 5°, to the solution obtained, which is cooled to 0°.When the introduction operation is terminated, the reaction mixture isagain stirred for 1 hour 30 minutes at 0°, then the excess magnesium isdestroyed by slowly adding iced water and finally the mixture is pouredinto 1,000 ml of water saturated with ammonium chloride, which inducescrystallisation. The compound is recrystallised from the minimumquantity of ethyl acetate and 2.5 g (yield 47%) of1,2,3,3a,4,5-hexahydro-3,6-dimethyl-6-hydroxy-6H-indolo[3,2,1-de][1,5]naphthyridineare collected, melting at 194°.

EXAMPLE 81,2,3,3a-Tetrahydro-3,6-dimethyl-4H-indolo[3,2,1-de][1,5]naphthyridine(method H)

[R₁ =CH₃, R₂ =H, R₃ =CH₃, R₄ and R₅ =an additional bond and R₆ =H]

4 g (0.0156 mol) of1,2,3,3a,4,5-hexahydro-3,6-dimethyl-6-hydroxy-6H-indolo[3,2,1-de][1,5]naphthyridine,60 ml of anhydrous benzene and 60 ml of pyridine are stirred in a 250 mlflask, until a solution is obtained, and 4 ml of phosphorus oxychlorideare added. The flask is then closed with a calcium chloride guard tube.Stirring is continued for 2 hours at 25° and the precipitate obtained ispoured into 1,500 ml of water.

The organic phase is decanted off, the aqueous phase is extracted twice,each time with 200 ml of benzene, and the organic solutions arecombined, washed with water, dried over sodium sulphate, filtered andfinally evaporated to dryness. A resin is thus obtained which is firsttreated with petroleum ether, it is then recrystallised from the minimumquantity of diisopropyl ether and 1.2 g (yield 32%) of1,2,3,3a-tetrahydro-3,6-dimethyl-4H-indolo[3,2,1-de][1,5]naphthyridine,melting at 89°, are collected.

EXAMPLE 9N-Cyclopropyl-1,2,3,3a,4,5-hexahydro-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-4-carboxamide(method L)

[R₁ =R₂ =H, R₃ and R₄ =O, R₅ =H, ##STR8##

0.011 mol of anhydrous pyridine (namely 0.9 ml) is added to 3 g of1,2,3,3a,4,5-hexahydro-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-4-carboxylicacid (cis-isomer prepared in accordance with scheme K) in suspension in100 ml of dichloroethane. The reaction flask is plunged into an icebath. After a few moments, 1 ml of thionyl chloride (0.011 mol) isadded, the flask is withdrawn from the ice bath and the mixture isstirred for 2 hours 30 minutes at normal temperature (with a calciumchloride guard tube).

Thereafter 0.33 mol of cyclopropylamine (about 22 ml) is added and themixture is again stirred for 2 hours 30 minutes. Finally, after theaddition of a solution of 100 ml of 0.5 N NH₄ OH, the mixture is stirredand decanted, and the aqueous solution is extracted 3 times, each timewith 100 ml of methylene chloride. The organic solutions are combined,washed with water, dried over sodium sulphate and evaporated, afterfiltration.

800 mg ofN-cyclopropyl-1,2,3,3a,4,5-hexahydro-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-4-carboxamideare collected, melting at 230° C.

EXAMPLE 10 Methyl1,2,3,3a,4,5-hexahydro-6-oxo-10-fluoro-6H-indolo[3,2,1-de][1,5]naphthyridine-4-carboxylate(method A₂)

[R₁ =H, R₂ =10-F, R₃ and R₄ =O, R₅ =H, R₆ =COOCH₃ -2 stereoisomers].

5-Fluoro-tryptamine is liberated by shaking, in a separating funnel, asuspension of 9.1 g (0.042 mol) of 5-fluoro-tryptamine hydrochloride inwater and ether, in the presence of dilute ammonia. The phases areseparated and the ether phase is washed with water and then dried overNa₂ SO₄. The ether is evaporated in vacuo. Traces of water are removedby distillation with benzene in vacuo. The resulting oil is dissolved in150 cm³ of anhydrous ether. 10 g of molecular sieve 4 A (Merck) areintroduced and then 9 g (0.044 mol) of diethyl α-formylsuccinate areadded. The reaction mixture is maintained at ambient temperature for onenight, with stirring. The sieve is removed by filtration. A current ofhydrogen chloride gas is bubbled through the filtrate, which induces alight chestnut-coloured gummy precipitation which solidifies slowly aswhite crystals. The mixture is stirred for 30 minutes after the end ofthe bubbling operation and then the ether is removed by suction. Theprecipitate is suspended in 50 cm³ of anhydrous methanol and 25 cm³ ofconcentrated H₂ SO₄ are added with stirring. The mixture is heated at100° C. for 1 hour. The mixture is cooled by immersion in a bath of icedwater and then poured into crushed ice. The pH of the mixture is madealkaline by the addition of the required quantity of ammonia. Themixture is extracted with methylene chloride, washed with water, driedover Na₂ SO₄ and then evaporated in vacuo. 9.1 g of a solid residue areobtained (yield 70%).

This is chromatographed on 600 g of silica gel (Merck 60, 0.063 - 0.2mm) in a 7:3 mixture of methylene chloride and acetone.

The least polar product, compound A, represents 3.6 g (yield 27%).

The most polar product, compound B, represents 2.8 g (yield 21%).

Compounds A and B are separately recrystallised from the minimumquantity of ethyl acetate. A provides 2.8 g (yield 22%) of the expectedcompound, melting point=172° C. It corresponds to the trans-H_(3a) -H₄isomer. B provides 1.9 g (yield 15%), melting point=214° C. Itcorresponds to the cis-H_(3a) -H₄ isomer.

                                      TABLE I                                     __________________________________________________________________________     ##STR9##                                                                                                                             Characteristics       Compound                                        Base or Melting point         No.    R.sub.1      R.sub.2                                                                            R.sub.3                                                                           R.sub.4                                                                           R.sub.5                                                                         R.sub.6  Method                                                                            Salt    (°C.)          __________________________________________________________________________    1 (Example 1)                                                                        CH.sub.3     H    O       H COOCH.sub.3                                                                            A.sub.2                                                                           m.s. cis                                                                              >270                                                                  m.s. trans                                                                            257-258               2 (Example 3)                                                                        CH.sub.3     H    O       H H        B   base    95                                                                    m.s.    188                   3      C.sub.2 H.sub.5                                                                            H    O       H H        B   base    114                   4 (Example 4)                                                                         ##STR10##   H    O       H H        C   base    126                   5      C.sub.6 H.sub.5 CH.sub.2                                                                   H    O       H H        D   base    174                                                                   m.s.    227-230               6 (Example 5)                                                                        CH.sub.2 CH.sub.2 CN                                                                       H    O       H H        DE  base    156                   7 (Example 6)                                                                        C.sub.6 H.sub.5 CO                                                                         H    O       H H        F   base    171-2                 8 (Example 7)                                                                        CH.sub.3     H    CH.sub.3                                                                          OH  H H        G   base    194                   9 (Example 8)                                                                        CH.sub.3     H    CH.sub.3                                                                          bond  H        H   base    89                    10     CH.sub.3     H    CH.sub.3                                                                          H   H H        I   base    110                   11     H            CH.sub.3 (10)                                                                      O       H H        A.sub.1                                                                           base    170-2                 12     n-C.sub. 3 H.sub.7                                                                         H    O       H H        B   base    111-113               13     i-C.sub. 3 H.sub.7                                                                         H    O       H H        D   base    161                   14     CH.sub.3 CO  H    O       H H        F   base    174                   15                                                                                    ##STR11##   H    O       H H        F   base    134                   16                                                                                    ##STR12##   H    O       H H        D   base    160                   17                                                                                    ##STR13##   H    O       H H        D   base    165                   18                                                                                    ##STR14##   H    O       H H        D   base    148                   19     CH.sub.2CH.sub.2COOCH.sub.3                                                                H    O       H H        E   base    122-125               20     CH.sub.3     CH.sub.2 (10)                                                                      O       H H        B   base    108-109               21     C.sub.2 H.sub.5                                                                            H    CH.sub.3                                                                          OH  H H        C   base    193-194               22     n-C.sub. 3 H.sub.7                                                                         H    CH.sub.3                                                                          OH  H H        G   base    210                   23     CH.sub.3     H    C.sub.2 H.sub.5                                                                   OH  H H        G   base    190                   24                                                                                    ##STR15##   H    CH.sub.3                                                                          OH  H H        G   base    175                   25     CH.sub.2C.sub.6 H.sub.5                                                                    H    CH.sub.3                                                                          OH  H H        G   base    175-177               26     C.sub.2 H.sub.5                                                                            H    CH.sub.3                                                                          Bond  H        H   base    89                    27                                                                                    ##STR16##   H    CH.sub.3                                                                          Bond  H        H   base    74                    28     C.sub.2 H.sub.5                                                                            H    CH.sub.3                                                                          H   H H        I   base    106                                                                   m.s.    215                   29                                                                                    ##STR17##   H    CH.sub.3                                                                          H   H H        I                                 30     CH.sub.3     H    O       H COOC.sub.2 H.sub.5                                                                     A.sub.2                                                                           base    162                                                                   m.s.    250                                                                   (3a,4H,H-cis)                                                                 base                                                                          (3a,4-H,H-trans                                                                       116                   31     CH.sub.3     H    O       H COO-n-C.sub. 3 H.sub.7                                                                 A.sub.2                                                                           base    150                                                                   m.s.    252                                                                   (3a,4-H,H-cis)                32     CH.sub.3     H    O       H COO-n-C.sub. 4 H.sub.9                                                                 A.sub.2                                                                           base    135                   33     CH.sub.2 CH.sub.2 COCH.sub.3                                                               H    O       H H        E   base    100                   34     CH.sub.2 COOC.sub.2 H.sub.5                                                                H    O       H H        D   m.s.    203                   35     CH.sub.2 CH.sub.2 CHOHCH.sub.3                                                             H    O       H H        J   base,                                                                         isomer A                                                                              144                                                                   base,                                                                         isomer B                                                                              115                   36     H            H    O       H COOH     K   base    >250                  37(Exam-                                                                      ple 9) H            H    O       H                                                                                ##STR18##                                 38     CH.sub.3     CH.sub.3 O(10)                                                                     O       H H        B   m.s.    245-6                 39(Exam-                                                                      ple 2) H            H    O       H COOCH.sub.3                                                                            A.sub.2                                                                           base    195                                                                   (3a,4-H,H cis)                                                                m.s.                                                                          (3a,4-H,H                                                                             26lns                 40     H            H    O       H COOC.sub.2 H.sub.5                                                                     A.sub.2                                                                           m.s.    243                                                                   (3a,4-H,H cis)                                                                m.s.    268                                                                   (3a,4-H,H trans)              41     C.sub.2 H.sub.5                                                                            H    O       H COOCH.sub.3                                                                            D   m.s.    223                                                                   (3a,4-H,H cis)                42     C.sub.2 H.sub.5                                                                            H    O       H COO C.sub.2 H.sub.5                                                                    D   m.s.    231                                                                   (3a,4-H,Hcis)                 43                                                                                    ##STR19##   H    O       H COO CH.sub.3                                                                           D   m.s.    220                                                                   (3a,4-H,Hcis)                 44     CH.sub.3     H    O       H COOH     K   base    280                                                                   (3a,4-H,Hcis)                 45     CH.sub.3     H    O       H CO NH.sub.2                                                                            L   base    >280                                                                  (3a,4-H,Hcis)                 46     CH.sub.3     H    O       H CO NH CH.sub.3                                                                         L   base    182                                                                   (3a,4-H,Hcis)                 47     CH.sub.3     H    O       H CO N(CH.sub.3).sub.2                                                                   L   base    251                                                                   (3a,4-H,Hcis)                 48     CH.sub.3     H    O       H                                                                                ##STR20##                                                                             L   base    170                                                                   (3a,4-H,Hcis)                 49     CH.sub.2 CH.sub.2 COCH.sub.3                                                               H    O       H COO CH.sub.3                                                                           E   m.s.    173                                                                   (3a,4-H,Hcis)                                                                 m.s.    160                                                                   (3a,4-H,Htrans)               50                                                                                    ##STR21##   H    O       H COO CH.sub.3                                                                           J   base    231                                                                   (3a,4-H,Hcis)                                                                 isomer A                                                                      base    198                                                                   (3a,4-H,Hcis)                                                                 isomer B                                                                      base                                                                          (3a,4-H,Htrans)                                                                       198                   51     H            Cl(10)                                                                             O       H COO CH.sub.3                                                                           D   base    191                   52     H            Cl(10)                                                                             O       H H        A.sub.1                                                                           base    161-3                 53     CH.sub.3     Cl(10)                                                                             O       H H        B   base    118-9                 54     H            F(10)                                                                              O       H H        A.sub.1                                                                           base    123-5                 55     CH.sub.3     F(10)                                                                              O       H H        B   base    146-7                 56     CH.sub.2CH.sub.2 COCH.sub.3                                                                Cl(10)                                                                             O       H H        E   base    135-6                 57     CH.sub.2CH.sub.2 COCH.sub.3                                                                F(10)                                                                              O       H H        E   base    124-5                 58     H            Cl(10)                                                                             O       H COOCH.sub.3                                                                            A.sub.2                                                                           base    162                                                                   (3a,4-H-trans)                                                                (3a,4-H-trans)                                                                base    209                                                                   (3a,4-H-cis)                  59     H            F(10)                                                                              O       H COOCH.sub.3                                                                            A.sub.2                                                                           base    172                   (Example                                        (3a,4-H,-trans)               10)                                             base    214                                                                   (3a,4-H-cis)                  60     CH.sub.3     F(10)                                                                              O       H COOCH.sub.3                                                                            B   base    189                                                                   (3a,4-H,trans)                                                                base    237                                                                   (3a,4-H-cis)                  61     CH.sub.3     Cl(10)                                                                             O       H COOCH.sub.3                                                                            B   base    215                                                                   (3a,4-H-trans)                                                                base    270                                                                   (3a,4-H-cis)                  62     CH.sub.2 COCH.sub.3                                                                        H    O       H H        D   base    135-6                 63     CH.sub.2 CHOHCH.sub.3                                                                      H    O       H H        J   base    164,5-165,5                                                           (isomer A)                                                                    base    142-143                                                               (isomer B)                    64     CH.sub.2CH.sub.2COCH.sub.3                                                                 CH.sub.3(10)                                                                       O       H H        D   base    120-1                 65     H            Cl (11)                                                                            O       H H        Al  base    145-6                 66     CH.sub.3     Cl (9)                                                                             O       H H        B   base    168-9                 67     CH.sub.2 CH.sub.2 COOCH.sub.3                                                              F (10)                                                                             O       H H        D   base    140-42                68     CH.sub.2 CH.sub.2 COOCH.sub. 3                                                             Cl (10)                                                                            O       H H        D   base    113-4                 69     CH.sub.3     CH.sub.3 (9)                                                                       O       H H        B   base    145-51 (d)            70     C.sub.2 H.sub.5                                                                            Cl (10)                                                                            O       H H        D   base    124-5                 71     CH.sub.2C.sub.6 H.sub.5                                                                    H    CH.sub.3                                                                          BOND                                                                              H H            base    64-7                  72     H            CL (9)                                                                             O       H H        Al  base    195-6                 73     H            CH.sub.3 (8)                                                                       O       H H        Al  base    76-8                  __________________________________________________________________________     m.s. = methanesulphonate                                                 

The compounds of the invention have been subjected to a pharmacologicalstudy.

1. TOXICITY

The 50 percent lethal dose (LD₅₀) of the compounds is determined formice of strain CD 1 by a graphical method.

The results are indicated in Table II below, for a representative numberof compounds.

2. ANOXIA DUE TO PRESSURE REDUCTION

Mice of the CD 1 strain are kept in an atmosphere depleted in oxygen, bysetting up a partial vacuum (190 mm. of mercury, corresponding to 5.25%of oxygen).

The survival time of the animals is noted. This time is increased by theagents capable of favouring oxygenation in the tissues and, inparticular, in the brain. The compounds studied are administeredintraperitoneally in several doses 10 minutes before the experiment. Thepercentage increases of the survival time relative to the valuesobtained with control animals are calculated. The mean active dose(MAD), namely the dose which increases the survival time by 100%, isdetermined graphically.

The results are indicated in Table II below for a representative numberof compounds.

3. ACTION ON THE DURATION OF THE "SLEEP" INDUCED BY SODIUM4-HYDROXY-BUTYRATE

This action was determined from the influence of the compounds on theduration of the "sleep" induced by sodium 4-hydroxy-butyrate (GHB) incurarised rats.

The animals used are male rats of the Charles River strain, weighing200±20 g. The animals, curarised by alloferin given intraperitoneally atthe rate of 1 mg/kg, are placed under artificial respiration by means ofa mask applied over the snout (respiration frequency: 40/minute; volumerespired: 14 cc). The oesophagus is ligatured beforehand so as to avoidair entering the stomach.

Fronto-parietal and occipital cortical electrodes make it possible torecord the electrocorticographic activity on a Grass model 79P polygraphat a speed of 6 mm/sec. The animals are prepared under local anaesthesia(2% xylocaine). The rats are kept at a constant temperature (37.5° C.)throughout the experiment. Ten minutes after the end of the preparationof the rat, a dose of 200 mg/kg of Na 4-hydroxybutyrate is injectedintravenously into the tail.

Doses of 10 and 30 mg/kg of the compounds to be studied are administeredintraperitoneally 3 minutes after the administration of the sodium4-hydroxy-butyrate.

The traces are evaluated for periods of 15 minutes over the course of 75minutes after the injection of "GHB". During this period of analysis,the total duration of the "sleep" is determined. A series of 15comparisons makes it possible precisely to define the duration of the"GHB sleep".

The statistical analysis of the results is carried out with the aid ofthe Mann-Whitney "U" test.

The results are reported in Table III below.

                  TABLE II                                                        ______________________________________                                                    ACUTE                                                                         TOXICITY    ANOXIA DUE TO                                                     LD.sub.50 (mg/kg)                                                                         PRESSURE                                                          for intraperi-                                                                            REDUCTION                                                         toneal administ-                                                                          intraperitoneal                                       COMPOUND    ration      administration                                        ______________________________________                                        2 (base     85          6                                                     2 (m.s.)    52          4.5                                                   9           78          6.5                                                   3           58          9                                                     10          50          6.5                                                   21          75          7                                                     26          67          10                                                    22          105         8                                                     28 (m.s.)   40          4.5                                                   30 (m.s.)   110         9                                                     1 (m.s.cis) 170         4                                                     33          170         8                                                     35 (base, isomer A)                                                                       150         9                                                     38          65          8                                                     52          165         9.5                                                   53          150         8                                                     62          190         10                                                    ______________________________________                                    

                                      TABLE III                                   __________________________________________________________________________             TOXICITY                                                                      (mg/kg  ACTIVITY                                                                  intra-    dose, mg/kg,                                                                         TOTAL DURATIN                                                                            DIFFERENCE IN                                 intra-                                                                            perit-                                                                            number of                                                                           given intra-                                                                         in minutes.                                                                              % RELATIVE TO                        COMPOUND venous                                                                            oneal                                                                             animals                                                                             peritoneally                                                                         seconds    THE CONTROLS                         __________________________________________________________________________    COMPARISON       15    --     54.12 ± 2.07                                                                          --                                   11       105 155 6     30     34.08 ± 1.21                                                                          -37                                  19 m.s.  103 680 6     30     38.59 ± 1.20                                                                          -28                                  1 trans m.s.                                                                            47 185 3     40     32.01 ± 2.59                                                                          -41                                  49 m.s.cis                                                                             --  600 6     30     38.51 ± 3.12                                                                          -28                                                   6     10     35.22 ± 2.26                                                                          -35                                  52       110 165 6     30     32.35 ± 5.02                                                                          -40                                                   6     10     37.34 ± 3.35                                                                          -31                                  54       --  100 6     30     28.28 ± 4.28                                                                          -47                                                   6     10     40.01 ± 5.00                                                                          -26                                  56       --  575 6     30     30.39 ± 3.01                                                                          -43                                                   6     10     43.07 ± 3.26                                                                          -20                                  51       --  760 6     30     37.51 ± 2.12                                                                          -30                                  63        75 125 6     30     34.52 ± 2.14                                                                          -36                                  isomer A                                                                      58 cis-  --  190 6     30     36.08 ± 2.47                                                                          -33                                  isomer                                                                        58 trans-                                                                              --  170 6     30     31.12 ± 2.18                                                                          -42                                  isomer                                                                        60 cis-  --  725 6     10     34.22 ± 2.47                                                                          -37                                  isomer                                                                        65       --   54 6     10     34.51 ± 1.42                                                                          -36                                  69       --   88 6     10     29.46 ± 1.27                                                                          -45                                  __________________________________________________________________________

The pharmacological study of the compounds of the invention shows thatthey are active in the test on anoxia due to pressure reduction, inmice, whilst only being slightly toxic and that they exert a significantwakening action in the test on "sleep" induced by sodium4-hydroxy-butyrate.

The compounds of the invention, which possess both an anti-anoxiaactivity and a psychotropic activity, can be used in therapy for thetreatment of disturbances of alertness, in particular to combatdisturbances of behaviour attributable to damage to the cerebral vesselsand to cerebral sclerosis in geriatrics, as well as for the treatment ofabsence due to cranial traumatisms, and the treatments of states ofdepression.

The invention consequently comprises all pharmaceutical compositionswhich contain the compounds and/or their salts as active principles, inassociation with any excipient appropriate for their administration, inparticular their oral or parenteral administration.

The methods of administration can be oral and parenteral.

The daily posology can range from 10 to 100 mg.

We claim:
 1. A compound of the formula: ##STR22## wherein R₁ is --(C₁₋₂alkylene)COO(C₁₋₂ alkyl) or --(C₁₋₂ alkylene)CO(C₁₋₂ alkyl); orhydrogen;R₂ is hydrogen, halogen, methyl, or methoxy;provided that whenR₁ is hydrogen, R₂ is neither hydrogen nor 10-methoxy in the form of aracemate or optical isomer thereof, or a pharmaceutically acceptablesalt of said compound.
 2. A compound of the formula ##STR23## wherein R₁is hydrogen, alkyl of 1 to 4 carbon atoms, 3-oxobutyl, 3-hydroxybutyl,2-oxopropyl, 2-hydroxypropyl or methoxycarbonylethyl;R₂ is hydrogen,halogen, methyl or methoxy; and R₆ is methoxycarbonyl, ethoxycarbonyl orcyclopropyl-aminocarbonyl;in the form of a racemate or optically activeform thereof, or a pharmaceutically acceptable salt of said compound. 3.A compound of claim 2, wherein R₂ is chlorine or fluorine. 4.1,2,3,3a,4,5-Hexahydro-3-(3-oxo-butyl)-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridineor a pharmaceutically acceptable salt thereof. 5.1,2,3,3a,4,5-Hexahydro-3-(2-oxo-propyl)-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridineor a pharmaceutically acceptable salt thereof. 6.1,2,3,3a,4,5-Hexahydro-6-oxo-10-chloro-6H-indolo[3,2,1-de][1,5]naphthyridineor a pharmaceutically acceptable salt thereof. 7.1,2,3,3a,4,5-Hexahydro-6-oxo-10-fluoro-6H-indolo[3,2,1-de][1,5]naphthyridineor a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition capable of providing an anti-anoxia or a psychotropiceffect, which comprises an amount of a compound of claim 1 capable ofproviding said effect.
 9. A method of providing a subject with ananti-anoxia effect which comprises treating said subject with an amountof a compound of claim 1 capable of providing said anti-anoxia effect.10. A method of providing a subject with psychotropic effect whichcomprises treating said subject with an amount of a compound of claim 1capable of providing said psychotropic effect.
 11. A method of providinga subject with an anti-anoxia effect which comprises treating saidsubject with an amount of a compound of claim 2 capable of providingsaid anti-anoxia effect.
 12. A method of providing a subject with ananti-anoxia effect which comprises treating said subject with an amountof1,2,3,3a,4,5-Hexahydro-3-(3-oxo-butyl)-6-oxo-6-6H-indolo[3,2,1-de][1,5]naphthyridinecapable of providing said anti-anoxia effect.
 13. A method of providinga subject with an anti-anoxia effect which comprises treating saidsubject with an amount of1,2,3,3a,4,5-Hexahydro-6-oxo-10-chloro-6H-indolo[3,2,1-de][1,5]naphthyridinecapable of providing said anti-anoxia effect.